Current scientific evidence points to the presence of cells originating from the periodontal ligament, wound stability, space provision, and primary intention healing, as fundamental biologic and clinical factors that must be met to obtain periodontal regeneration. Only a profound understanding of biological and clinical variables affecting the outcome of periodontal regenerative procedures will allow clinicians to manipulate biological and clinical factors effectively in order to optimize the clinical result and increase the predictability of periodontal-regenerative therapy.